Substituted biphenyl compounds

ABSTRACT

The invention relates to compound of formula (I)  
                 
wherein: 
         B represents hydrogen, COOR, CONRR′, or (C 1 -C 6 )alkyl substituted by COOR, CONRR′, or OR,    G 1  represents —X′—(CH 2 ) n —X—(CH 2 ) m —X″— chain wherein X, X′, X″, n and m are as defined in the description, 
 
Cy represents a grouping of formula (II) or (III):  
                 
   G 2  represents alkylene chain as defined in the description, and A represents NRCOR′, NRCSR′, CONRR′, CSNRR′, NRCONR′R″, or NRCSNR′R″. and medicinal products containing the same which are useful in treating or preventing melatoninergic disorders.

FIELD OF THE INVENTION

The present invention relates to new substituted biphenyl compounds to aprocess for their preparation and to pharmaceutical compositionscontaining them.

In view of their novel structure, the compounds of the present inventionare new and they exhibit pharmacological properties of great interest inrelation to melatoninergic receptors.

DESCRIPTION OF THE PRIOR ART

There are known from the literature indolic biphenyl compounds that areuseful as metalloprotease inhibitors (WO 96 15096) or specific ligandsof 5HT-1B and 5HT-1D receptors (WO 95 01334).

Also, benzimidazolic biphenyl compounds are described in PatentApplication EP 468 470 as angiotensin inhibitors.

BACKGROUND OF THE INVENTION

In the last ten years, numerous studies have demonstrated the major roleplayed by melatonin (N-acetyl-5-methoxytryptamine) in a large number ofphysiopathological phenomena and in the control of the circadian rhythm,but melatonin has a rather short half-life owing to the fact that it israpidly metabolised. Great interest therefore lies in the possibility ofmaking available to the clinician melatonin analogues that aremetabolically more stable and have an agonist or antagonist characterand of which the therapeutic effect may be expected to be superior tothat of the hormone itself.

In addition to their beneficial action in respect of circadian rhythmdisorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders(Psychopharmacology, 1990, 100, pp. 222-226), ligands of themelatoninergic system have valuable pharmacological properties inrespect of the central nervous system, for example anxiolytic andantipsychotic properties (Neuropharmacology of Pineal Secretions, 1990,8 (3-4), pp. 264-272), and analgesic properties (Pharmacopsychiat.,1987, 20, pp. 222-223), and also for the treatment of Parkinson'sdisease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer's disease(Brain Research, 1990, 528, pp. 170-174). Such compounds have alsodemonstrated activity in relation to certain cancers (Melatonin—ClinicalPerspectives, Oxford University Press, 1988, pp. 164-165), ovulation(Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology,1986, 24, pp. 359-364), and in the treatment of obesity (InternationalJournal of Eating Disorders, 1996, 20 (4), pp. 443-446).

Those various effects are exerted via the intermediary of specificmelatonin receptors. Molecular biology studies have demonstrated theexistence of a number of receptor sub-types that are capable of bindingthat hormone (Trends Pharmacol. Sci., 1995, 16, p. 50 WO 97.04094). Ithas been possible for some of those receptors to be located andcharacterised for different species, including mammals. In order to beable to understand the physiological functions of those receptorsbetter, to have specific ligands available is of great interest.Moreover such compounds, by interacting selectively with one or anotherof those receptors, may be excellent medicaments for the clinician inthe treatment of pathologies associated with the melatoninergic system,some of which have been mentioned above.

In addition to being new, the compounds of the present invention exhibita very strong affinity for melatonin receptors and/or a selectivity forone or another of the melatoninergic receptor sub-types.

DETAILED DESCRIPTION OF THE INVENTION

More especially, the present invention relates to compounds of formula(I):

wherein:

-   -   B represents a hydrogen atom, a COOR group, a CONRR′ group, or a        linear or branched (C₁-C₆)alkyl group substituted by a COOR,        CONRR′ or OR group (wherein R and R′, which may be identical or        different, each represents a hydrogen atom, or a group linear or        branched (C₁-C₆)alkyl, linear or branched (C₂-C₆)alkenyl, linear        or branched (C₂-C₆)alkynyl, aryl, aryl-(C₁-C₆)alkyl in which the        alkyl moiety may be linear or branched, heteroaryl,        heteroaryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear        or branched, polyhalo-(C₁-C₆)alkyl in which the alkyl moiety may        be linear or branched, (C₃-C₈)cycloalkyl or        (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety may be        linear or branched, it being possible in addition for R and R′        to form, together with the nitrogen atom carrying them, a        morpholinyl, piperidyl, piperazinyl or pyrrolidinyl group),    -   G₁ represents a —X′—(CH₂)_(n)—X—(CH₂)_(m)—X″— chain wherein        -   X represents an oxygen or sulphur atom, or a CH₂ or NR group            (wherein R is as defined hereinbefore),        -   X′ and X″, which may be identical or different, each            represents an oxygen or sulphur atom or an NR group (wherein            R is as defined hereinbefore),        -   n and m, which may be identical or different, each            represents 0, 1, 2, 3, 4 or 5, it being understood that it            is not possible to have two consecutive hetero atoms and            that the chain so defined may contain one or more            unsaturations,    -   Cy represents a grouping of formula (II)        -   wherein D represents a phenyl or a pyridine, W represents an            oxygen or sulphur atom, or a CH₂ or NR group (wherein R is            as defined hereinbefore), R₁ represents a halogen atom or an            R, OR or COOR group (wherein R is as defined hereinbefore)            and the representation            denotes that the bond is single or double, it being            understood that the valency of the atoms is respected,    -   or a grouping of formula (III)    -   wherein R₁ and the representation        are as defined hereinbefore    -   G₂ represents a chain containing from 1 to 6 carbon atoms that        is optionally substituted by one or more groups selected from R,        OR, COR, COOR (wherein R is as defined hereinbefore) and halogen        atoms,    -   and A represents a NRCOR′, NRCSR′, CONRR′, CSNRR′, NRCONR′R″ or        NRCSNR′R″ group (wherein R and R′ are as defined hereinbefore        and R″ may have the same meanings as R and R′),        wherein:    -   “aryl” is to be understood as meaning a phenyl or naphthyl group        that is unsubstituted or substituted by one or more identical or        different groups selected from R, OR, COR, COOR, NRR′ (wherein R        and R′ are as defined hereinbefore), nitro, cyano and halogen        atoms,    -   “heteroaryl” is to be understood as meaning any mono- or        bi-cyclic group having from 5 to 10 ring members and capable of        containing from 1 to 3 hetero atoms selected from oxygen,        sulphur and nitrogen, that group being unsubstituted or        substituted by one or more identical or different groups        selected from R, OR, COR, COOR, NRR′ (wherein R and R′ are as        defined hereinbefore), nitro, cyano and halogen atoms,        to their enantiomers and diastereoisomers and also to addition        salts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned byway of non-limiting example hydrochloric, hydrobromic, sulphuric,phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic,camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned byway of non-limiting example sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc.

Preferred compounds of the invention are compounds of formula (I)wherein B represents:

-   -   a COOR group wherein R is preferably a hydrogen atom or a linear        or branched (C₁-C₆)alkyl group, such as, for example, methyl,    -   or a linear or branched (C₁-C₆)alkyl group substituted by a COOR        or OR group, more especially COOH, alkyloxycarbonyl, OH or        alkoxy.

The preferred G₁ group of the compounds of the invention is the group—O—(CH₂)_(p)—O— wherein p is an integer such that 0<p<6, such as, forexample, —O—(CH₂)₄—O—.

The invention relates more especially to compounds of formula (I)wherein Cy represents a naphthalene, tetrahydronaphthalene,benzothiophene, benzofuran, indole, indene or azaindole group.

G₂ prefereably represents a —(CH₂)₂— or —(CH₂)₃— group.

Preferred meanings for A are the groups NRCOR′ and CONRR′, moreespecially the groups NHCOR′ and CONHR.

Even more especially, the invention relates to the following compoundsof formula (I):

-   methyl    4′-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate,-   4′-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylic    acid,-   N-{2-[7-(4-{[4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl]oxy}butoxy)-1-naphthyl]ethyl}-acetamide,-   N-(2-{7-[4-([1,1′-biphenyl]-4-yloxy)butoxy]-1-naphthyl}ethyl)acetamide,-   N-(2-{7-[4-([1,1′-biphenyl]-3-yloxy)butoxy]-1-naphthyl}ethyl)acetamide.

The enantiomers, diastereoisomers and also addition salts with apharmaceutically acceptable acid or base of the preferred compounds ofthe invention form an integral part of the invention.

The present invention relates also to a process for the preparation ofthe compounds of formula (I), which process is characterised in thatthere is used as starting material a compound of formula:MeO-Cy-G₂-A  (IV)wherein A, G₂ and Cy are as defined for formula (I),which is subjected to demethylation using conventional agents, such asHBr, AlCl₃, AlBr₃, BBr₃ or Lewis acid/nucleophile binary systems such asAlCl₃/PhCH₂SH or BBr₃/Me₂S, for example, to obtain a compound of formula(V):HO-Cy-G₂-A  (V)wherein A, G₂ and Cy are as defined hereinbefore,which is converted in conventional manner

-   -   by the action of sodium N,N-dimethylthiocarbamate for example,        to the corresponding thiol of formula (VI):        HS-Cy-G₂-A  (VI)    -   wherein A, G₂ and Cy are as defined hereinbefore,    -   or to the corresponding amine compound of formula (VII):        RNH-Cy-G₂-A  (VII)    -   wherein A, G₂, Cy and R are as defined hereinbefore,        the compounds of formula (V), (VI) and (VII) representing the        compound of formula (VIII):        HX″-Cy-G₂-A  (VIII)        wherein Cy, G₂, X″ and A are as defined hereinbefore,        which compound of formula (VIII) is condensed with a compound of        formula (IX):        wherein Hal represents a bromine, chlorine or iodine atom, and        X, n and m are as defined for formula (I), (it being understood        that it is not possible to have two consecutive hetero atoms and        that the chain so defined may contain one or more        unsaturations),        to yield a compound of formula (X):        HO—(CH₂)_(n)—X—(CH₂)_(n)—X″-Cy-G₂-A  (X)        wherein A, G₂, Cy, X, X″, n and m are as defined hereinbefore        (it being understood that it is not possible to have two        consecutive hetero atoms in the        HO—(CH₂)_(n)—X—(CH₂)_(m)—X″—chain and that the chain so defined        may contain one or more unsaturations),        the hydroxy function of which is converted in conventional        manner into a leaving group; such as, for example, a mesylate, a        tosylate, or a halogenated compound, to yield a compound of        formula (X′):        E-(CH₂)_(n)—X—(CH₂)_(m)—X″-Cy-G₂-A  (X′)        wherein A, G₂, Cy, X, X″, n and m are as defined hereinbefore        and E represents a mesyl or tosyl group or a halogen atom,        which is reacted in basic medium with a compound of formula        (XI):        B′-Ph-Ph-X′H  (XI)        wherein X′ is as defined for formula (I), and B′ may have the        same meanings as B as defined for formula (I) with the exception        of the groups COOH and alkyl substituted by a COOH group,        to yield a compound of formula (I/a), a particular case of the        compounds of formula (I):        B′-Ph-Ph-G₁-Cy-G₂-A  (I/a)        wherein A, G₂, G₁, Cy and B′ are as defined hereinbefore,        the compound of formula (I/a) being subjected, when B′        represents a COOR₁′ group or alkyl substituted by a COOR₁′ group        (wherein R₁′ may have any of the meanings of R defined        hereinbefore with the exception of a hydrogen atom), to        hydrolysis to yield a compound of formula (I/b), a particular        case of the compounds of formula (I):        B″-Ph-Ph-G₁-Cy-G₂-A  (I/b)        wherein A, G₂, G₁ and Cy are as defined hereinbefore, and B″        represents a COOH group or alkyl substituted by a COOH group,        the totality of the compounds (I/a) and (I/b) constituting the        compounds of formula (I) which may, if desired, be purified by a        conventional purification technique, are optionally separated        into their isomers according to a conventional separation        technique and, if desired, are converted into addition salts        with a pharmaceutically acceptable acid or base.

The compounds of formula (IV) are readily obtainable by the personskilled in the art according to methods described in the literature.

The compounds of the invention and pharmaceutical compositionscontaining them have proved to be useful in the treatment of disordersof the melatoninergic system.

A pharmacological study of the compounds of the invention has in factdemonstrated that they are non-toxic, have a high affinity for melatoninreceptors and have substantial activity in respect of the centralnervous system and the microcirculation, enabling it to be establishedthat the products of the invention are useful in the treatment ofstress, sleep disorders, anxiety, seasonal affective disorders,cardiovascular pathologies, pathologies of the digestive system,insomnia and fatigue due to jetlag, schizophrenia, panic attacks,melancholia, appetite disorders, obesity, insomnia, pain, psychoticdisorders, epilepsy, diabetes, Parkinson's disease, senile dementia,various disorders associated with normal or pathological aging,migraine, memory losses, Alzheimer's disease, and in cerebralcirculation disorders. In another field of activity, it appears that theproducts of the invention can be used in the treatment of sexualdysfunctions, that they have ovulation-inhibiting and immunomodulatingproperties and that they are capable of being used in the treatment ofcancers.

The compounds will preferably be used in the treatment of seasonalaffective disorders, sleep disorders, cardiovascular pathologies,insomnia and fatigue due to jetlag, appetite disorders and obesity.

For example, the compounds will be used in the treatment of seasonalaffective disorders and sleep disorders.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) on its own or incombination with one or more pharmaceutically acceptable excipients.

Amongst the pharmaceutical compositions according to the invention theremay be mentioned more especially those which are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration, especially tablets or dragées, sublingualtablets, sachets, paquets, gelatin capsules, glossettes, lozenges,suppositories, creams, ointments, dermal gels and drinkable orinjectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the route of administration, the nature of the therapeutic indication orpossibly associated treatments, and ranges from 0.01 mg to 1 g per 24hours in one or more administrations.

The following Examples illustrate the invention but do not limit it inany way. The following Preparations result in compounds of the inventionor in synthesis intermediates useful in the preparation of theinvention.

Preparation 1: N-[2-(7-Hydroxy-1-naphthyl)ethyl]acetamide

Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethylsulphide complex are dissolved in 100 ml of dichloromethane and stirredfor 15 minutes at ambient temperature. A solution of 13.7 mmol ofN-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethaneis added, and the reaction mixture is heated at reflux for 30 hours.After cooling, the reaction mixture is cautiously hydrolysed and thedichloromethane is evaporated off. The mixture is then extracted withethyl acetate and the combined organic phases are washed with an aqueous1M potassium hydrogen carbonate solution. The organic phase is driedover magnesium sulphate and concentrated to yield the title compound.White solid.

Melting point: 125-126° C.

By proceeding as in Preparation 1, using as starting material theappropriate substrate, Preparations 2 to 14 are obtained:

Preparation 2: N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]acetamidePreparation 3:N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamidePreparation 4: N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-2-furamidePreparation 5: N-[2-(7-Hydroxy-1-naphthyl)ethyl]butanamide Preparation6: N-[2-(5-Hydroxy-1-benzothien-3-yl)ethyl]acetamide Preparation 7:N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]cyclopropane-carboxamidePreparation 8: N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]acetamide Preparation9: N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]acetamidePreparation 10: N-[2-(7-Hydroxy-1-naphthyl)ethyl]cyclobutanecarboxamidePreparation 11:2,2,2-Trifluoro-N-[2-(7-hydroxy-1-naphthyl)ethyl]acetamide Preparation12: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-furamide Preparation 13:N-[2-(2-Benzyl-5-hydroxy-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]-acetamidePreparation 14: N-[2-(5-Hydroxy-1H-inden-3-yl)ethyl]pentanamidePreparation 15: N-[2-(5-Mercapto-1-benzofuran-3-yl)ethyl]acetamide

The product obtained in Preparation 2 (9 mmol) is added, with stirring,to a solution of potassium hydroxide (10 mmol) dissolved in 15 ml ofwater and 16 ml of tetrahydrofuran. The solution is cooled using anice/salt bath, and dimethylthiocarbamoyl chloride (9 mmol) dissolved intetrahydrofuran (15 ml) is added dropwise with stirring. After stirringfor half an hour while keeping cold, the reaction mixture is extractedwith chloroform. The organic phases are combined, dried over magnesiumsulphate, filtered and then concentrated under reduced pressure. Theresidue is taken up in diphenyl ether (10 ml) and heated at reflux forone hour under a nitrogen atmosphere. The diphenyl ether is evaporatedoff under reduced pressure until a solution of approximately 2 ml isobtained. The 2 ml of distillate are cautiously poured, while still hot,into 50 ml of hexane to yield, after cooling, a solid isolated byfiltration. The solid so obtained is added to a solution of potassiumhydroxide (380 mg) dissolved in a water/methanol (1 ml/10 ml) mixture.The solution is heated at reflux for 12 hours and then cooled andconcentrated under reduced pressure. The residue is taken up in 20 ml ofchloroform and extracted 3 times with water. The organic phase is driedover magnesium sulphate, filtered and concentrated under reducedpressure. The residue is chromatographed on silica gel to yield thetitle product.

Preparation 16: N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]acetamide Step A:N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]acetamide

Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured into a150 ml three-necked flask equipped with a dropping funnel, a condenseron top of which is mounted a tube filled with calcium chloride, and amechanical stirrer. The solution is cooled using an ice-bath whilemaintaining stirring, and bromine (10 mmol) is added. When the additionis complete, the ice-bath is removed and then the product obtained inPreparation 2 (8 mmol) is added. The reaction mixture is stirred at60-70° C. until the starting material has disappeared. At the end of thereaction, the mixture is filtered, and then the filtrate is concentratedunder reduced pressure. The residue is taken up in ethyl acetate, washedwith water and then with a saturated potassium hydrogen carbonatesolution, and once again with water, and then dried over magnesiumsulphate and concentrated under reduced pressure. The residue isfiltered over silica gel to yield the title product.

Step B: N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]acetamide

A mixture of the product obtained in Step A (2 mmol), potassium iodide(30 mmol) and copper(I) iodide (10 mmol) in hexamethylphosphoramide (6ml) is heated at 150-160° C. with stirring, under a nitrogen atmosphere,until a 90% conversion rate has been reached. Dilute hydrochloric acidis then added, followed by ether, and the mixture is then filtered toremove the insoluble copper(I) salts. The organic phase is separatedoff, washed with a solution of sodium sulphite and with water, driedover magnesium sulphate and evaporated to yield a residue which ischromatographed on silica gel to yield the title product.

Step C: N-[2-(5-Vinyl-1-benzofuran-3-yl)ethyl]acetamide

15 mmol of the product obtained in Step B, 16 mmol of vinyltributyltinand 0.43 mmol of tetrakis(triphenylphosphine)palladium are heated for 3hours at 110° C., with stirring, in 30 ml of N-methylpyrrolidinone.After removal of the solvent by evaporation, the residue is taken up in20 ml of dichloromethane and treated with an aqueous 10% potassiumfluoride solution. Extraction, concentration under reduced pressure andchromatography on silica gel yield the pure title product.

Step D: N-[2-(5-Formyl-1-benzofuran-3-yl)ethyl]acetamide

1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g ofsodium periodate are added at ambient temperature to a solution of 10mmol of the product obtained in Step C in a mixture of 50 ml of dioxaneand 25 ml of water. After stirring overnight at ambient temperature, thesuspension is filtered and the filtrate is concentrated under reducedpressure. The resulting residue is taken up in dichloromethane. Theorganic phase is washed with water, dried and evaporated. The residue ispurified by chromatography on silica gel to yield the title product.

Step E: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid

2.7 g of potassium permanganate in 50 ml of an acetone/water mixture(50/50) are added at ambient temperature to a solution of 6.88 mmol ofthe product obtained in Step D in 30 ml of acetone. The solution isstirred for 2 hours at ambient temperature and then filtered. Thefiltrate is concentrated under reduced pressure and chromatographed onsilica gel to yield the title product.

Step F: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid chloride

5 mmol of the product obtained in Step E are dissolved in 40 ml ofthionyl chloride. After stirring under an inert atmosphere for 1 hour,the thionyl chloride is removed by evaporation under reduced pressure toyield the title product.

Step G: N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]acetamide

A solution of the product obtained in Step F (20 mmol) indichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) iscooled in an ice-bath. After the addition of sodium azide (25 mmol)dissolved in 5 ml of water, the solution is stirred vigorously at 0° C.for 2 hours. The organic phase is separated off, washed with water (2×5ml) and dried over magnesium sulphate. After filtration, trifluoroaceticacid (30 mmol) is added and the solution is stirred under reflux for 60hours. After cooling, the organic phase is washed with a saturatedsodium hydrogen carbonate solution (2×5 ml) and concentrated underreduced pressure. The residue is then taken up in methanol (20 ml), andwater (80 ml) and then potassium carbonate (30 mmol) are added. Afterstirring at ambient temperature for 20 hours, the reaction mixture isconcentrated under reduced pressure to a volume of about 60 ml, and isthen extracted 3 times with ether (3×50 ml). After drying over sodiumsulphate, the organic phase is filtered and then evaporated underreduced pressure. The residue is chromatographed on silica gel to yieldthe title product.

Preparation 17: N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]-2-furamide

The procedure is as in Preparation 16 starting from the compoundobtained in Preparation 4.

Preparation 18:N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]-acetamide

The procedure is as in Preparation 1.

Preparation 19:N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

The procedure is as in Preparation 1.

Preparation 20:N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[3,2-b]pyrid-3-yl)ethyl]-acetamide

The procedure is as in Preparation 1.

EXAMPLE 1 Methyl4′-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylateStep A: N-{2-[7-(2-Bromoethoxy)naphth-1-yl]ethyl}cetamide

The compound obtained in Preparation 1 (0.009 mol) is dissolved in 20 mlof a mixture of dimethyl sulphoxide (6 ml) and butanone (14 ml). 0.027mol of potassium carbonate and 0.036 mol of dibromoethane are added, andthe mixture is heated at reflux for 48 hours. The reaction mixture isthen cooled and poured into water. The aqueous phase is extracted withEt₂O, and then the organic phase is washed with water until the washingwaters are neutral, and subsequently dried over magnesium sulphate andevaporated under reduced pressure. The resulting residue is purified bychromatography on silica gel (eluant: acetone/cyclohexane (2/8)) andrecrystallized. White solid.

Melting point: 1110-111° C.

Elemental microanalysis: % C H N Calculated: 57.15 5.40 4.17 Found:57.28 5.38 3.91

Step B: Methyl4′-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylate

In a 100 ml round-bottomed flask, 0.003 mol of methyl4′-hydroxy[1,1′-biphenyl]-4-carboxylate and 0.003 mol of the compoundobtained in Step A are dissolved in a mixture of 3 ml of dimethylsulphoxide and 20 ml of butanone. 0.009 mol of potassium carbonate andone potassium iodide crystal are added and then the mixture is heated atreflux for 12 hours. The reaction mixture is then cooled and poured into100 ml of water. The precipitate that forms is suctioned off andrecrystallized to yield the title product.

EXAMPLE 24′-[2-({8-[2-(Acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylicacid

In a 100 ml round-bottomed flask, 19 mmol of the compound obtained inExample 1 are suspended in 25 ml of THF, and then 15 ml of methanol, 15ml of water and 38 mmol of sodium hydroxide are added. The reactionmixture is maintained at ambient temperature with stirring for 10 hours.The solution is subsequently concentrated, poured into water and thenacidified with 12M HCl. The precipitate obtained is filtered off, washedwith water and recrystallized to yield the title product.

EXAMPLE 3 Methyl4′-[2-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 2.

EXAMPLE 4 Methyl4′-{2-[(3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl)oxy]ethoxy}-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 3.

EXAMPLE 5 Methyl4′-[2-({3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 4.

EXAMPLE 6 Methyl4′-[2-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}amino)-ethoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 16.

EXAMPLE 7 Methyl4′-[2-({8-[2-(butyrylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 5.

EXAMPLE 8 Methyl4′-[2-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 6.

EXAMPLE 9 Methyl4′-{2-[(3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo-[2,3-b]pyrid-5-yl)oxy]ethoxy}-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of theproduct obtained in Preparation 1 by the compound obtained inPreparation 7.

EXAMPLE 10N-{2-[7-(2-{[4′-(Hydroxymethyl)-[1,1′-biphenyl]-4-yl]oxy}ethoxy)-1-naphthyl]ethyl}acetamide

The procedure is as in Example 1, with the replacement in Step B ofmethyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate by4′-(hydroxymethyl)-[1,1′-biphenyl]-4-ol.

EXAMPLE 11 Methyl4′-[2-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}oxy)ethoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 1, with the replacement in Step A of thecompound obtained in Preparation 1 by the compound obtained inPreparation 8.

EXAMPLE 124′-[2-({3-[2-(Acetylamino)ethyl]-1H-indol-5-yl}oxy)ethoxy-]-[1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 11.

EXAMPLE 13 Methyl4′-[3-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)propoxy]-[1,1′-biphenyl]-4-carboxylateStep A: N-{2-[7-(3-Hydroxypropyloxy)naphth-1-yl]ethyl}acetamide

In a 100 ml round-bottomed flask, 0.022 mol of the compound obtained inPreparation 1 is dissolved in 30 ml of dimethylformamide. 0.066 mol ofpotassium carbonate and 0.033 mol of 3-bromopropan-1-ol are added, andthen the mixture is heated at 80° C. for 4 hours. The reaction mixtureis cooled and poured into 100 ml of a 1M HCl solution. The aqueous phaseis extracted 3 times with Et₂O and then the organic phase is dried overMgSO₄ and evaporated under reduced pressure. The title product isobtained by recrystallization. White solid.

Melting point: 141-142° C.

Step B: 3-({8-[2-(Acetylamino)ethyl]-2-naphthyl}oxy)propylmethanesulphonate

In a 250 ml round-bottomed flask, the alcohol obtained in Step A isdissolved in 50 ml of dichloromethane, and 0.012 mol of triethylamine isadded. The mixture is cooled in an ice/salt bath at −10° C., and then0.012 mol of mesyl chloride is added dropwise with magnetic stirring.The reaction mixture is stirred at ambient temperature for 4 hours. 100ml of water are then added, followed by extraction with CH₂Cl₂. Theorganic phase is washed with water, dried over MgSO₄ and evaporatedunder reduced pressure. The resulting oil is purified by chromatographyon silica gel (eluant: acetone/cyclohexane (2/8)).

Step C: Methyl4′-[3-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)propoxy]-[1,1′-biphenyl]-4-carboxylate

In a 100 ml round-bottomed flask containing 30 ml of methanol, 0.06 g ofsodium is added in small portions. When the sodium has been completelyused up, 0.0033 mol of methyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate isadded and the mixture is stirred for 20 minutes. The methanol is removedby evaporation under reduced pressure, the residue is taken up in 15 mlof DMF, and then 0.0027 mol of the compound obtained in Step B is added.The reaction mixture is then heated at reflux for 12 hours andsubsequently cooled and poured into 100 ml of water and 10 ml of 3M HCl.After extraction with ethyl acetate, the organic phase is washed with a10% sodium hydroxide solution and then with water. After drying overMgSO₄ and removal of the solvent by evaporation under reduced pressure,the title compound is purified by chromatography on silica gel.

EXAMPLE 14 Methyl4′-{3-[(8-{2-[(cyclobutylcarbonyl)amino]ethyl}-2-naphthyl)oxy]-propoxy}-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 13, starting from the compound obtainedin Preparation 10.

EXAMPLE 15 Methyl4′-[3-({3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl}amino)-propoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 13, starting from the compound obtainedin Preparation 17.

EXAMPLE 164′-[3-({3-[2-(2-Furoylamino)ethyl]-1-benzofuran-5-yl}aminopropoxy]-1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 15.

EXAMPLE 17 Methyl4′-{3-[(8-{2-[(trifluoroacetyl)amino]ethyl}-2-naphthyl)oxy]-propoxy}-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 13, with the replacement of the compoundof Preparation 1 by the compound of Preparation 11.

EXAMPLE 184′-{3-[(8-{2-[(Trifluoroacetyl)amino]ethyl}-2-naphthyl)oxy]propoxy}-[1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 17.

EXAMPLE 19 Methyl4′-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylateStep A: N-{2-[7-(4-Bromobutoxy)-1-naphthyl]ethyl}acetamide

The procedure is as in Step A of Example 1, with the replacement ofdibromoethane by 1,4-dibromobutane.

Step B: Methyl4′-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Step B of Example 1.

White solid.

Melting point: 166-168° C.

Elemental microanalysis: % C H N Calculated: 74.61 6.45 2.72 Found:74.62 6.48 2.81

EXAMPLE 204′-[4-({8-[2-(Acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 19.

White solid.

Melting point: 223-225° C.

Elemental microanalysis: % C H N Calculated: 70.83 5.94 2.66 Found:71.16 6.05 2.69

EXAMPLE 21N-{2-[7-(4-{[4′-(Hydroxymethyl)-[1,1′-biphenyl]-4-yl]oxy}butoxy)-1-naphthyl]ethyl}acetamide

The procedure is as in Example 19, with the replacement in Step B ofmethyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate by4′-(hydroxymethyl)-[1,1′-biphenyl]-4-ol.

Beige solid.

Melting point: 172-173° C.

Elemental microanalysis: % C H N Calculated: 76.99 6.88 2.90 Found:76.74 6.70 3.12

EXAMPLE 22N-(2-{7-[4-([1,1′-Biphenyl]-4-yloxy)butoxy]-1-naphthyl}ethyl)-acetamide

The procedure is as in Example 19, with the replacement in Step B ofmethyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate by (1,1′-biphenyl)-4-ol.

White solid.

Melting point: 138-140° C.

Elemental microanalysis: % C H N Calculated: 79.44 6.89 3.10 Found:79.19 6.93 3.24

EXAMPLE 23N-(2-{7-[4-([1,1′-Biphenyl]-3-yloxy)butoxy]-1-naphthyl}ethyl)-acetamide

The procedure is as in Example 19, with the replacement in Step B ofmethyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate by (1,1′-biphenyl)-3-ol.

White solid.

Melting point: 111-112° C.

Elemental microanalysis: % C H N Calculated: 79.44 6.89 3.10 Found:79.23 6.79 3.21

EXAMPLE 24 Methyl4′-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)-butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 2.

EXAMPLE 25 Methyl4′-[4-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)-butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 6.

EXAMPLE 26 Methyl4′-[4-({3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyrid-5-yl}-oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 9.

EXAMPLE 274′-[4-({3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 24.

EXAMPLE 284′-[4-({3-[2-(Acetylamino)ethyl]-1-benzothien-5-yl}oxy)butoxy[1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 25.

EXAMPLE 294′-[4-({3-[2-(Acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyrid-5-yl}oxy)-butoxy]-[1,1′-biphenyl]-4-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 26.

EXAMPLE 30 Methyl4′-[4-({3-[2-(acetylamino)ethyl]-2-benzyl-1H-pyrrolo[2,3-b]pyrid-5-yl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 13.

EXAMPLE 31 Methyl4′-[4-({8-[2-(2-furoylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 12.

EXAMPLE 32 Methyl4′-[4-({3-[2-(pentanoylamino)ethyl]-1H-inden-5-yl}oxy)-butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 14.

EXAMPLE 33 Methyl4′-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}thio)-butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 15.

EXAMPLE 34 Methyl4′-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[2,3-b]pyrid-5-yl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 18.

EXAMPLE 35 Methyl3′-[4-({8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-3-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 19.

EXAMPLE 363′-[4-({8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}-oxy)butoxy]-[1,1′-biphenyl]-3-carboxylicacid

The procedure is as in Example 2, starting from the compound obtained inExample 35.

EXAMPLE 37 Ethyl4′-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2b]pyrid-5-yl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylate

The procedure is as in Example 19, starting from the compound obtainedin Preparation 20 and ethyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate.

Melting point: 145-146° C.

Elemental microanalysis: % C H N Calculated: 70.30 6.66 7.93 Found 69.846.67 7.94

Pharmacological Study EXAMPLE A Acute toxicity study

Acute toxicity was evaluated after oral administration to groups eachcomprising 8 mice (26±2 grams). The animals were observed at regularintervals during the course of the first day, and daily for the twoweeks following treatment. The LD₅₀ (the dose that causes the death of50% of the animals) was evaluated and demonstrated the low toxicity ofthe compounds of the invention.

EXAMPLE B Melatonin Receptor Binding Study on Pars tuberalis Cells ofSheep

Melatonin receptor binding studies of the compounds of the inventionwere carried out according to conventional techniques on Pars tuberaliscells of sheep. The Pars tuberalis of the adenohypophysis is in factcharacterised in mammals by a high density of melatonin receptors(Journal of Neuroendocrinology, 1, pp. 1-4, 1989).

Protocol

-   1) Sheep Pars tuberalis membranes are prepared and used as target    tissue in saturation experiments to determine the binding capacities    and affinities for 2-[¹²⁵I]-iodomelatonin.-   2) Sheep Pars tuberalis membranes are used as target tissue in    competitive binding experiments using the various test compounds in    comparison with melatonin.

Each experiment is carried out in triplicate and a range of differentconcentrations is tested for each compound. The results, afterstatistical processing, enable the binding affinities of the compoundtested to be determined.

Results

The compounds of the invention appear to have a strong affinity formelatonin receptors.

EXAMPLE C Melatonin MT₁ and MT₂ Receptor Binding Study

The MT₁ or MT₂ receptor binding experiments are carried out using2-[¹²⁵I]-iodomelatonin as reference radioligand. The radioactivityretained is determined using a liquid scintillation counter.

Competitive binding experiments are then carried out in triplicate usingthe various test compounds. A range of different concentrations istested for each compound. The results enable the binding affinities ofthe compounds tested (IC₅₀) to be determined.

Thus, the IC₅₀ values found for the compounds of the invention showbinding for one or other of the MT₁ and MT₂ receptor sub-types, thosevalues being ≦10 μM.

EXAMPLE D Action of the Compounds of the Invention on the CircadianRhythms of Locomotive Activity of the Rat

The involvement of melatonin in influencing the majority ofphysiological, biochemical and behavioural circadian rhythms byday/night alternation has made it possible to establish apharmacological model for research into melatoninergic ligands.

The effects of the compounds are tested in relation to numerousparameters and, in particular, in relation to the circadian rhythms oflocomotive activity, which are a reliable indicator of the activity ofthe endogenous circadian clock.

In this study, the effects of such compounds on a particularexperimental model, namely the rat placed in temporal isolation(permanent darkness) are evaluated.

Experimental protocol

One-month-old male rats are subjected, as soon as they arrive at thelaboratory, to a light cycle of 12 hours of light per 24 hours (LD12:12).

After 2 to 3 weeks' adaptation, they are placed in cages fitted with awheel connected to a recording system in order to detect the phases oflocomotive activity and thus monitor the nychthemeral (LD) or circadian(DD) rhythms.

As soon as the rhythms recorded show a stable pattern in the light cycleLD 12:12, the rats are placed in permanent darkness (DD).

Two to three weeks later, when the free course (rhythm reflecting thatof the endogenous clock) is clearly established, the rats are given adaily administration of the compound to be tested.

The observations are made by means of visualization of the rhythms ofactivity:

-   -   influence of the light rhythm on the rhythms of activity,    -   disappearance of the influence on the rhythms in permanent        darkness,    -   influence by the daily administration of the compound transitory        or durable effect.

A software package makes it possible:

-   -   to measure the duration and intensity of the activity, the        period of the rhythm of the animals during free course and        during treatment,    -   optionally to demonstrate by spectral analysis the existence of        circadian and non-circadian (for example ultradian) components.        Results

The compounds of the invention clearly appear to have a powerful actionon the circadian rhythm via the melatoninergic system.

EXAMPLE E Light/Dark Cage Test

The compounds of the invention are tested on a behavioural model, thelight/dark cage test, which enables the anxiolytic activity of thecompounds to be revealed.

The equipment comprises two polyvinyl boxes covered with Plexiglas. Oneof the boxes is in darkness. A lamp is placed above the other box,yielding a light intensity of approximately 4000 lux at the centre ofthe box. An opaque plastic tunnel separates the light box from the darkbox. The animals are tested individually for a session of 5 minutes. Thefloor of each box is cleaned between each session. At the start of eachtest, the mouse is placed in the tunnel, facing the dark box. The timespent by the mouse in the illuminated box and the number of passagesthrough the tunnel are recorded after the first entry into the dark box.

After administration of the compounds 30 minutes before the start of thetest, the compounds of the invention significantly increase the timespent in the illuminated cage and the number of passages through thetunnel, which demonstrates the anxiolytic activity of the compounds ofthe invention.

EXAMPLE F Activity of the Compounds of the Invention on the CaudalArtery of the Rat

The compounds of the invention were tested in vitro on the caudal arteryof the rat. Melatoninergic receptors are present in those vessels, thusproviding a relevant pharmacological model for studying melatoninergicligand activity. The stimulation of the receptors can induce eithervasoconstriction or dilation depending upon the arterial segmentstudied.

Protocol

One-month-old rats are habituated to a light/darkness cycle of 12 h/12 hfor a period of 2 to 3 weeks.

After sacrifice, the caudal artery is isolated and maintained in ahighly oxygenated medium. The arteries are then cannulated at both ends,suspended vertically in an organ chamber in a suitable medium andperfused via their proximal end. The pressure changes in the perfusionflow enable evaluation of the vasoconstrictive or vasodilatory effect ofthe compounds.

The activity of the compounds is evaluated on segments that have beenpre-contracted by phenylephrine (1 μM). A concentration/response curveis determined non-cumulatively by the addition of a concentration of thetest compound to the pre-contracted segment. When the effect observedreaches equilibrium, the medium is changed and the preparation is leftfor 20 minutes before the addition of the same concentration ofphenylephrine and a further concentration of the test compound.

Results

The compounds of the invention significantly modify the diameter ofcaudal arteries pre-constricted by phenylephrine.

EXAMPLE G Pharmaceutical Composition: Tablets

1000 tablets each containing a dose of 5 g 5 mg of4′-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1′-biphenyl]-4- carboxylic acid (Example 20)Wheat starch 20 g Maize starch 20 g Lactose 30 g Magnesium stearate 2 gSilica 1 g Hydroxypropyl cellulose 2 g

1. A compound selected from those of formula (I):

wherein B represents hydrogen, COOR, CONRR′, or linear or branched(C₁-C₆)alkyl substituted by COOR, CONRR′, or OR wherein R and R′, whichmay be identical or different, each represents hydrogen, or linear orbranched (C₁-C₆)alkyl, linear or branched (C₂-C₆)alkenyl, linear orbranched (C₂-C₆)alkynyl, aryl, aryl-(C₁-C₆)alkyl in which the alkylmoiety may be linear or branched, heteroaryl, heteroaryl-(C₁-C₆)alkyl inwhich the alkyl moiety may be linear or branched, polyhalo-(C₁-C₆)alkylin which the alkyl moiety may be linear or branched, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety may belinear or branched, it being possible in addition for R and R′ to form,together with the nitrogen carrying them, morpholinyl, piperidyl,piperazinyl, or pyrrolidinyl, G₁ represents an—X′—(CH₂)_(n)—X—(CH₂)_(m)—X″— chain wherein X represents CH₂, X′ and X″,which may be identical or different, each represents oxygen or sulphur,n and m, which may be identical or different, each represents 0, 1, 2,3, 4 or 5, it being understood that it is not possible to have twoconsecutive hetero atoms in the chain and that the chain so defined maycontain one or more unsaturations, Cy represents a group of formula (II)

wherein D represents phenyl or pyridine, W represents oxygen, sulphur,CH₂, or NR, wherein R is as defined hereinbefore, R₁ represents halogen,R, OR, or COOR, wherein R is as defined hereinbefore and therepresentation

denotes that the bond is single or double, it being understood that thevalency of the atoms is respected, G₂ represents a 1 to 6 carbon atomchain containing that is optionally substituted by one or more groupsselected from R, OR, COR, COOR, wherein R is as defined hereinbefore,and halogen, and A represents NRCOR′, NRCSR′, CONRR′, CSNRR′, NRCONR′R″,or NRCSNR′R″, wherein R and R′ are as defined hereinbefore and R″ mayhave the same meanings as R and R′, wherein: “aryl” is to be understoodas meaning phenyl or naphthyl that is unsubstituted or substituted byone or more identical or different groups selected from R, OR, COR,COOR, NRR′, wherein R and R′ are as defined hereinbefore, nitro, cyanoand halogen, “heteroaryl” is to be understood as meaning any mono- orbi-cyclic group having from 5 to 10 ring members and capable ofcontaining from 1 to 3 hetero atoms selected from oxygen, sulphur, andnitrogen, that group being unsubstituted or substituted by one or moreidentical or different groups selected from R, OR, COR, COOR, NRR′,wherein R and R′ are as defined hereinbefore, nitro, cyano, and halogen,its enantiomers and diastereoisomers, and also addition salts thereofwith a pharmaceutically acceptable acid or base.
 2. A compound of claim1, wherein B represents COOR.
 3. A compound of claim 2, wherein Rrepresents hydrogen.
 4. A compound of claim 2, wherein R representslinear or branched (C₁-C₆)alkyl.
 5. A compound of claim 1, wherein Brepresents linear or branched (C₁-C₆)alkyl substituted by COOR.
 6. Acompound of claim 1, wherein B represents linear or branched(C₁-C₆)alkyl substituted by OR.
 7. A compound of claim 1, wherein G₁represents —O—(CH₂)_(p)—O— in which p is an integer such that 0<p<6. 8.A compound of claim 1, wherein A represents NHCOR.
 9. A compound ofclaim 1, which is selected from ethyl4′-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2-b]pyrid-5-yl}oxy)butoxy]-[1,1′-biphenyl]-4-carboxylateand addition salts thereof with a pharmaceutically-acceptable acid orbase.
 10. A method for treating a living animal body, including a human,afflicted with a disorder of the melatoninergic system, comprising thestep of administering to the living animal body, including a human, anamount of a compound of claim 1 which is effective for the alleviationof the disorder.
 11. A pharmaceutical composition comprising as activeprinciple an effective amount of a compound of claim 1, together withone or more pharmaceutically-acceptable excipients or vehicles.